Exposure of mammalian cells to ionizing radiation leads primarily to DNA damage-induced cell death. The induction of apoptosis by ionizing radiation represents an alternative mode to cell kill. Breakdown of sphingomyelin to produce ceramide by activation of sphingomyelinase is one of the upstream signalling cascades activated in apoptotic cells in response to stimuli such as TNF. Using genetic models of acid sphingomyelinase deficiency, the ceramide generated by radiation-induced activation of sphingomyelinase has been shown to serve as a second messenger in initiating an apoptotic response. PKC activation represents an upstream anti-apoptotic checkpoint at the sphingomyelinase level as well as a checkpoint downstream of ceramide generation. The balance between these pro- and anti-apoptotic systems may determine the magnitude of the observed apoptotic response.